Cortical GABA in MDD and Primary Insomnia with Magnetic Resonance Spectroscopy OBJECTIVE: To investigate GABA levels in anterior cingulate (ACC), parieto-occipital (POC) and frontal cortices (FC) in major depressive disorder (MDD) and primary insomnia with proton magnetic resonance spectroscopy imaging (1H MRS). BACKGROUND: The prevalence of MDD as well as its personal and societal costs have motivated over four decades of research into its pathophysiology and neurobiological correlates. Although the preponderance of studies have focused on the role of the biogenic amines and the hypothalamic-pituitary-adrenal (HPA) axis, recent evidence suggests that the neurotransmitter gamma-aminobutyric acid (GABA) may play a key role in the pathophysiology of MDD. Supporting this conclusion are recent studies utilizing proton magnetic resonance spectroscopy (1H-MRS), which permits in vivo analysis of brain neurochemistry. Most of these studies concurred in finding reduced GABA levels in multiple brain regions in MDD including the POC, ACC, and the FC. Recently, we utilized 1H-MRS to reveal GABA deficits in subjects with primary insomnia (PI), e.g., insomnia without other accompanying medical or psychiatric disorders. Relative to good sleeper controls, subjects with PI not only had reduced levels of GABA, but within subjects with PI, GABA levels correlated with polysomnographic (PSG) measures of sleep maintenance. The proposed study will test the hypothesis that GABA deficits in MDD in fact reflect the sleep disturbance characteristic of that disorder rather than the mood state per se. METHOD: We plan to perform 1H MRS imaging for GABA/creatine levels in the ACC, POC and FC in 50 subjects with MDD (half of whom will have insomnia and the other half will not), 25 subjects with PI (insomnia without mood disturbance) and 25 control subjects. All subjects will have sleep diaries and actigraphy for 2 weeks prior to their PSG and MRI. The primary endpoint, GABA levels, will be analyzed by repeated measures ANOVA (using linear mixed model) with diagnostic group (4 study groups) as the main effect and the 3 ROIs (POC, ACC, and FC) as repeats. We will also use regression analysis to correlate PSG and sleep diary information, with 1H MRS.